I. Field of the Invention
The present invention is broadly concerned with a new anti-thrombotic therapy and compounds useful for the new therapy. More particularly, the present invention relates to selective inhibitors of phosphoinositide (PI) 3-kinase β, use of the selective inhibitors in anti-thrombotic therapy and a screening method for a compound useful for the new anti-thrombotic therapy by detecting selective inhibitory activity of PI 3-kinase β of the compound.
II. Description of the Related Art
Platelets are specialized adhesive cells that play a fundamental role in the haemostatic process. Under normal conditions, platelets neither adhere to, nor are activated by the vascular endothelium. However, damage to the endothelium or disruption of plaque exposes the flowing blood to a variety of thrombogenic elements including collagen, fibronectin and von Willebrand factor (vWF). Circulating platelets bear receptors of these thrombogenic elements. Upon vascular injury, platelets, via glycoprotein GP Ib receptor, adhere to specific subendothelial adhesive proteins, such as von Willebrand factor (vWF) at the site of ruptured plaques (platelet adhesion), become activated (platelet activation), and produce a number of substances including adenosine diphosphate (ADP), thrombin, serotonin, and vasoconstrictor thromboxane A2 (TxA2). The activated ADP receptor in turn activates the GP IIb/IIIa receptor on the platelet surface. These receptors become the sites of fibrinogen bridges that link the platelets together (platelet aggregation) and subsequent thrombus formation.
Thus, sudden rupturing or fissuring of advanced atherosclerotic plaques causes an exaggerated platelet adhesion response, which commonly leads to the formation of vaso-occlusive platelet thrombi. The formation of these thrombi in the coronary or cerebral circulation leads to acute myocardial infarction and stroke, respectively, which combined represent the leading causes of death in the industrialized world. Platelet thrombus formation also leads to a number of other clinical states including unstable angina, sudden death, transient ischemic attacks, amaurosis fugax, and acute ischemia of limbs and internal organs. A number of factors that contribute to increase of thrombogenic potential of ruptured plaques include (1) the high reactivity of adhesive substrates in the plaque, (2) the presence of tissue factor in the lesion, and (3) the indirect platelet activating effects of high shear caused by narrowing of the vessel lumen by the atherothrombotic process.
The existing anti-thrombotic therapies mainly target one or more key steps in the thrombotic process. That is, anti-coagulants and anti-platelet agents are frequently used to alleviate thrombosis. Blood clotting can be minimized or eliminated in many instances by administering a suitable anti-coagulant, including one or more of a coumarin derivative (e.g., warfarin and dicumarol) or a charged polymer (e.g., heparin, hirudin or hirulog), or through the use of an anti-platelet agent (e.g, aspirin, clopidogrel, ticlopidine, dipyridimole, or one of several GPIIb/IIIa receptor antagonists). Anti-coagulants and platelet inhibitors suffer from a significant limitation, however, due to side effects such as hemorrhaging, re-occlusion, “white-clot” syndrome, irritation, birth defects, thrombocytopenia, and hepatic dysfunction. Moreover, long-term administration of anti-coagulants and platelet inhibitors can particularly increase risk of life-threatening illness or hemorrhage.
Thus, to avoid the aforementioned drawbacks of the existing anti-thrombotic therapy, there exists a need to develop a new anti-thrombotic therapy selectively targeting a process that is critical to pathological thrombus formation without interfering with normal haemostasis.
Rheological disturbances (high shear and turbulent flow) play a major role in promoting pathological thrombosis, and thus one such strategy would be to attenuate the platelet activating effects of high shear stress by targeting mechano-sensory elements in platelets. However, before the instant invention, signaling events that are important for shear-induced platelet activation, but not for haemostasis, have not been identified.